Latest / EHA Unplugged / MDS Pathophysiology and the Role of Immune Dysfunction (with Dr Shahram Kordasti)

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MDS Pathophysiology and the Role of Immune Dysfunction (with Dr Shahram Kordasti) · EHA Unplugged

• 0:07
  Greetings and welcome to EHA Unplugged, the official podcast
• 0:11
  channel of the European Hematology Association EHA.
• 0:15
  Hello. We're going today to talk about
• 0:19
  immunology and MD's. And I'm Kiersten Kreinbeck.
• 0:22
  I'm a Professor of hematology at Research Hospital at University
• 0:25
  of Copenhagen in Denmark. And I'm seeing MD's patients in
• 0:29
  the clinics. And I have a lab where we also
• 0:31
  work with MD's. And today, it's my privilege to
• 0:35
  welcome Shyam Kadasti. He is an Associate professor,
• 0:39
  the group leader in applied cancer in wounded pathology at
• 0:43
  King's College in London and an honorary clinical hematologist
• 0:47
  at Guy's Hospital in London. And Sharon Green has been
• 0:51
  working with immunology and MD's for many years, and he also has
• 0:56
  been working a lot with multidimensional cytometry.
• 0:59
  So welcome, Sharon. We're looking forward to hear
• 1:03
  your thoughts about MD's. Thanks, Kirsten, for for
• 1:07
  invitation and for the nice introduction.
• 1:11
  Yeah. So today we're going to talk
• 1:12
  about immunology MD's and as you mentioned and see what we know
• 1:21
  and what we don't know. Perhaps what we don't know is
• 1:23
  more than what we know. Despite several years of
• 1:26
  working, we know much more than what we used to at least.
• 1:29
  And that's a good news. Yeah.
• 1:32
  So I think now, you know, we've learned all these things about
• 1:35
  the mutations over the last 10 years and how important they are
• 1:38
  and that they start an early time point.
• 1:40
  So, So what is the, I mean, does does immunology really play a
• 1:45
  role and, and what's the hint and, and the egg in this
• 1:48
  situation? Can you elaborate a little bit
• 1:50
  on that maybe? Yeah, we get this question a lot
• 1:52
  and you're absolutely right. I think we may a huge progress
• 1:57
  in terms of understanding the photophysiology of MD's and
• 2:00
  especially with this IPSSM and generally more standardized way
• 2:05
  of looking at mutation, we have a better understanding of the
• 2:09
  events that happening in MD's. That's excellent.
• 2:13
  But I think that's not the whole story for several reasons.
• 2:18
  Of course there is no one reason and there is.
• 2:22
  This is a complex disease, a group of diseases.
• 2:25
  I have to say considering the new classification really we
• 2:29
  need to say that it's we are not talking about one disease, we're
• 2:32
  talking about the complex, several different conditions at
• 2:36
  least and each of them they have different interaction with
• 2:41
  immune system. So there are general evidence
• 2:45
  that for instance, the Karolinska study that published
• 2:49
  a few years ago, they look at the huge number of MD's on AML
• 2:53
  and they've shown that presence over to immunity or a chronic
• 2:58
  inflammation due to infection for instance, increase the risk
• 3:02
  of MD's on AML. So in the part of Physiology
• 3:05
  level at the, I mean epidemiology study, you can't
• 3:09
  see that other than that we and others, we have shown that both
• 3:15
  the innate immunity, myeloid, Dr. inflammation as well as
• 3:20
  adaptive immune response are important.
• 3:23
  They correlate with risk of disease progression.
• 3:28
  And in the photophysiology level with the specific mutation, you
• 3:32
  can see that they play a part. So.
• 3:38
  Can I ask one thing here? Because what about this
• 3:40
  inflammation you see? Is that produced by the mutated
• 3:43
  cells or is it already there? What do you think about that?
• 3:48
  Very good question and not easy to answer.
• 3:52
  I think there are. If I if you look at my first
• 3:56
  slide which basically summarises the MBS photophysiology, we have
• 4:03
  environmental factor, genetic and age itself play an important
• 4:07
  role in flammaging what we call play a role.
• 4:11
  Presence of some genomic background may play a role, but
• 4:16
  stomatic mutations, we have different groups of mutations.
• 4:20
  There are mutations that they contribute to the inflammation
• 4:25
  and some of them they are less important and some of them
• 4:29
  contribute to even a suppression for instance like TP 53.
• 4:34
  So we cannot give a general overview and say each mutation,
• 4:44
  all mutations they play same role and they contribute or not
• 4:48
  contributing the inflammation. Some of them they do, some are
• 4:51
  less likely. Yeah.
• 4:53
  Could you mention some of those that do contribute to
• 4:56
  inflammation just for understanding?
• 4:59
  For instance, there are a few that are less know about like
• 5:05
  ASXL one or SF3B1 but ASXL 1 is more likely to contribute.
• 5:12
  That's a very good question and and obviously not all the
• 5:15
  somatic mutations they play the same contribution or not.
• 5:21
  It's not one simple clause that we say OK this they do or not.
• 5:27
  But some of the mutation like U2AF1, it's been shown that they
• 5:32
  contribute in the pyroptosis and inflammation and some are less
• 5:41
  important or at least they are suggestion, although they are
• 5:45
  some controversial data. But that like SF3V1 that are
• 5:51
  less contributing to the inflammation and some of them
• 5:56
  not only not much related to inflammation, they contribute to
• 6:00
  the immunosuppression. And TP 53 for instance has been
• 6:05
  shown to expand the regulatory T cells and contribute to
• 6:11
  immunosuppression. So somatic mutation they have
• 6:15
  different roles, depends on which class of mutations they
• 6:18
  are coming from and some of them we don't know yet.
• 6:22
  But what about? I think also Ted 2, there's been
• 6:24
  a lot at least about, you know, they have this mouse model and
• 6:27
  stuff. Right.
• 6:27
  That's correct. That's correct.
• 6:29
  Exactly. So I'm not going to name all of
• 6:30
  them. You know, we are talking about
• 6:32
  40. Yeah, yeah.
• 6:34
  I agree, I'm thinking. And some of them we don't know,
• 6:36
  some we know, some of them. So still ongoing, but at least a
• 6:40
  few very important one. We know that they contribute
• 6:44
  differently, some they do, some they don't and they have
• 6:47
  different roles. So this what we call basically
• 6:54
  inflammation and myeloid drug inflammation is a important part
• 6:59
  of physiological aspects of MD's.
• 7:04
  And that's the next slide that I've shown that NLRP 3 pathway
• 7:08
  activation, pyroctosis and a vicious circle of cell death and
• 7:14
  contribution to inflammation. So if inflammation is so
• 7:18
  important, why it doesn't something like Prednisone work
• 7:21
  in MD's or doesn't? Yeah, it's a very good question.
• 7:25
  So first of all, this inflammation, it's when we talk
• 7:32
  about immune dysregulation, we're talking about a
• 7:35
  multifactorial immune response. And if you look at my next
• 7:42
  slide, the inflammation has short effect and longer term
• 7:47
  effect and in short term effect. So in short term, so at the very
• 7:53
  acute phase, we need the inflammation because it's
• 7:58
  weakening the immune response in infection, in cancer for cell
• 8:03
  death. So that is what we call the
• 8:05
  acute phase inflammation and it happens to all of us and it's
• 8:10
  always there. Cancer also at the earliest
• 8:12
  stage present and those are the inflammation.
• 8:15
  They respond very well. If you want to subside, whether
• 8:18
  it's good or bad is a different story, but they respond.
• 8:21
  But the inflammation level can go down and what we call it the
• 8:26
  smoldering inflammation, it's a smoldering inflammation.
• 8:29
  It's in the background, it's has Geno toxicity.
• 8:33
  It contribute and change the immune environment to
• 8:37
  immunosuppressive environment. This immunosuppressive
• 8:40
  environment is an environment that doesn't respond to
• 8:44
  classical immunosuppression techniques that we use.
• 8:49
  For instance, giving a steroid doesn't help in that environment
• 8:54
  you already have a immunosuppressed environment.
• 8:58
  Unfortunately, this inflammation is more harmful 1 and it's a
• 9:03
  smoldering that drive the ingeno toxicity and drive the malignant
• 9:08
  clone and controlling is is not that straightforward.
• 9:12
  You need to be more specific. Yeah, those are the targets.
• 9:16
  So the. Specific cells that that expand
• 9:19
  in that situation can you? Yeah, MBS is exactly MBS.
• 9:23
  CS can expand, T regs expand, exhaustion of T cell will happen
• 9:28
  on that environment. And these are basically the
• 9:33
  cornerstone of that immunosuppression and K cells
• 9:36
  become less effective in terms of their function.
• 9:40
  And so it's A and it's not just MD's.
• 9:44
  Remember this happens in most cancers.
• 9:48
  And as I show in the next slide, we have a stepwise from active
• 9:54
  immune response to more immunosuppressive environment
• 9:58
  and immune escape. And this immune escape happens
• 10:01
  in all cancer. MBS is not an exception.
• 10:05
  I've, I always found it very difficult to understand the
• 10:08
  switch. You know, we haven't low grade
• 10:09
  MBS to high grade MBS. I mean, what's driving that, do
• 10:12
  you think? Yeah.
• 10:14
  I think at that stage I think the other aspects like genetic
• 10:19
  become more important. I think initiation as you know
• 10:24
  not at least as far as we know not all high risk MD's coming
• 10:29
  from low risk necessarily. So depends on what genetic
• 10:33
  factor involve etcetera and not all low risk MD's go to high
• 10:38
  risk or all high risk MD's go to AM.
• 10:41
  And so of course, majority of them go on high risk.
• 10:44
  But what I'm trying to say is not necessarily a stepwise that
• 10:49
  we see in every single patient. So there are other factors
• 10:53
  involved, what mutations are exist, what environmental factor
• 10:58
  involved, all the rest are also important.
• 11:02
  So it's not just one factor, but from immunological point of
• 11:06
  view, definitely there is a switch of all of the
• 11:10
  inflammatory baby T cell response and you can see that
• 11:14
  some low risk and yes, they respond to ATG.
• 11:18
  For instance. Which you don't expect in a
• 11:22
  malignant disease to respond to ATG.
• 11:24
  So it, it means that at that stage we are talking about
• 11:27
  different and basically that brings me to the next slide that
• 11:34
  basically to think about the immune therapy.
• 11:41
  Perhaps you want to post OK if it's the case.
• 11:44
  Yeah, why doesn't it work then? Or does it work?
• 11:48
  Yes, it's, it's a good question because when we talk about this
• 11:52
  immune response in MD's, the first question that I asked, oh,
• 11:57
  we give checkpoints inhibitor, it doesn't work in MD's.
• 12:03
  I, I kind of, I need to remind ourselves as hematologists that
• 12:07
  we are the 1st that we actually did immunotherapy in human and
• 12:12
  we should be very proud of it. And that's stem cell transplants
• 12:16
  and give them a lot. These are, these are
• 12:18
  immunotherapy and cell therapy and very successful 1.
• 12:23
  And that's the. And the only one that can cure
• 12:26
  patients we should remember. It's only curative option and
• 12:30
  therefore as you can see in my next slide, we have a group of
• 12:34
  patients, a lot of them that they benefit from this type of
• 12:38
  immunotherapy. We should remember bone marrow
• 12:41
  transplant is a inducing the a, a immune response against
• 12:48
  leukemic clone and that is an immunotherapy awakening the
• 12:53
  immune response is a very important thing and we already
• 12:56
  doing it. So yes, we do immunotherapy in
• 13:00
  MD's and actually that's the only curative option but not for
• 13:05
  old patients for several reason. They don't have donor, they are
• 13:08
  not fit for transplant etcetera, etcetera.
• 13:11
  The other app option as I mentioned is the other group
• 13:16
  that some of them they need immunosuppression which is a bit
• 13:19
  a strange you need to give ATG or immunomodulatory it's a mite
• 13:24
  which again feels like OK, So what we are.
• 13:27
  Talking. But there was more than low
• 13:28
  risk, right? We're talking about now, right?
• 13:30
  Yeah. Where where you still have a
• 13:32
  very active immune system in a way.
• 13:34
  Exactly. Yeah, but.
• 13:36
  Even 5A SA hyperventilating agent, remember hyperventilating
• 13:40
  agent is not an immunomodulatory but it has immunomodulatory.
• 13:45
  Yeah, because it does up regulate some things.
• 13:47
  Exactly. So there are other factors and
• 13:50
  therefore if you look at my next slide, but I try to visualise
• 13:56
  here that when we talk about immune dysregulation, we're
• 14:00
  talking about a a spectrum between inflammatory or auto
• 14:06
  inflammatory diseases, true autoimmune diseases, autoimmune
• 14:12
  disease like IPEX is, is autoimmune disease T cell
• 14:15
  related is nothing to do with inflammation as such or when we
• 14:19
  go to St. syndrome. Or so it's the inner adversity
• 14:22
  adapted immune system. Vexus is very much inflammatory
• 14:26
  and not much T cell response as such.
• 14:29
  MD's sitting in in in the middle and in the middle.
• 14:33
  It means that it has elements of T cell response, autoimmunity
• 14:37
  and elements of inflammation. Some patients are closer to the
• 14:41
  autoimmune side, some patients closer to the auto inflammatory
• 14:45
  side. Those patients with suites, for
• 14:48
  instance, or those patients with hypoplastic MBS, not all of
• 14:52
  them. Some of the hypoplastic MBS
• 14:54
  perhaps are closer to the A, a side similar to.
• 14:59
  And we don't really, I mean it's not really used in the new
• 15:01
  classification all this is it or you know.
• 15:05
  No, not really, and that's something I think is missing.
• 15:08
  Yeah, I think so too, because how should we then figure out
• 15:11
  how to choose the the treatment? Yes, exactly.
• 15:15
  And if I revisit the question of treatment, my next slide shows
• 15:22
  that yes, checkpoint inhibitors are not very promising, but a
• 15:28
  few patients, a few percentage of patients, they respond, but
• 15:31
  what are they? Who are they?
• 15:33
  Do we have any criteria to predict who will respond?
• 15:38
  And then the next slide, I'm showing an array of
• 15:42
  immunotherapy methods that almost all of them are being
• 15:46
  used now in MD's clinical trial. My worries and that's a a worry
• 15:52
  that makes me a bit nervous because I'm worried that if we
• 15:56
  we choose our patients for this trial based on IPSSIPSSMIPSSR,
• 16:02
  whatever we do and based on that is nothing to do with the immune
• 16:07
  system. Now, therefore we choose this
• 16:09
  patient and we give them immunotherapy methods exactly we
• 16:15
  are choosing patients not suitable and therefore at the
• 16:19
  end we may get 5% respond, 10% respond and not.
• 16:22
  Very. Yeah.
• 16:22
  But there's a small group, right?
• 16:24
  So we have to. So we need to identify them and
• 16:27
  I think that is a very important and kind of crucial point that
• 16:35
  we need to highlight that it is important that in these patients
• 16:41
  we need a better approach and include other factors.
• 16:46
  Somatic mutations are absolutely important.
• 16:49
  Why talk whatever included in IPSS, they are shown to be
• 16:54
  important for the and it's validated for the survival.
• 17:00
  But here we are not talking about survival, we're talking
• 17:03
  about prediction. I don't think IPSSM even if good
• 17:08
  enough for predicting response term no.
• 17:12
  It's not validated for that either, is it?
• 17:14
  I mean, that was not that was not even the that.
• 17:16
  Was not the reason. No, no.
• 17:18
  So the next step I think is we need an additional approach and
• 17:23
  to have a combination of clinical data, somatic mutation,
• 17:29
  different omics study to look at immuno genome, microbiome,
• 17:37
  combination of all of these, scaled them and then have an
• 17:43
  other classification that it's designed for response to
• 17:47
  therapy, which we don't have at the moment.
• 17:50
  This is very interesting, Shan, But but how should we do that in
• 17:53
  the General Hospital? You know, it's I mean, it, it
• 17:57
  sounds like a complicated procedure.
• 17:58
  So how would how would clinicians?
• 18:01
  Yes, I think this is not something that we should expect
• 18:05
  the General Hospital or a hematology in the general
• 18:08
  hematologist in General Hospital.
• 18:11
  I think we need a collaborative study in big centres.
• 18:15
  With. As we did for the psoriatic
• 18:18
  mutation, it was several centre contributed and analysed.
• 18:24
  Sophisticated method go down to a list of genes that can be
• 18:30
  tested then in General Hospital in routine basis and it can be
• 18:36
  used. I think the same needs to
• 18:37
  applied here needs to be done sophisticated with all mixes
• 18:41
  study etcetera but not on day-to-day basis.
• 18:44
  You need one biggest study to do this and at the end of it we say
• 18:49
  OK, these are the factors that needs to be tested in routine
• 18:52
  lab. Yeah, or.
• 18:54
  Maybe you can make an algorithm or something like.
• 18:56
  That exactly an algorithm based on that and then come up with OK
• 19:00
  for each patient a few simple tests for inflammation and
• 19:05
  immune response for instance needs to be tested and once this
• 19:08
  done this is the algorithm OK, this kind of group of patient
• 19:13
  they are more inflammatory so so.
• 19:16
  We go for. Give them Iraq inhibitor, TLR 4
• 19:20
  inhibitor or something around that line.
• 19:23
  These patients are very immunogenic.
• 19:26
  It seems like they may have T cell response.
• 19:29
  Maybe they benefit from ATG, which we don't do much these
• 19:32
  days for. No, that's true.
• 19:35
  These other patients, well they are not really immunogenic.
• 19:39
  It seems like we should go for transplant or something on that
• 19:42
  line. What about what about
• 19:44
  vaccinations? Sharon, do you?
• 19:46
  Believe in that exactly there are as you know, there are
• 19:49
  studies at the moment that try to do this cell therapy based on
• 19:55
  new antigens that to do I think the early days.
• 20:00
  One aspect that we shouldn't remember, we should forget is
• 20:06
  the most we are talking about. We are not a confined tumor like
• 20:11
  solid tumors that malignant cells are not exposed to immune
• 20:16
  system. We are talking about an open
• 20:21
  malignancy. So all the cells are already
• 20:23
  exposed to immune system and the most immunogenic clones were
• 20:28
  already eradicated. So this the remaining one are
• 20:33
  they have to be less immunogenic otherwise they would have been
• 20:37
  eradicated. So to reinstate immune response.
• 20:41
  So or they managed to suppress immune response in a way to not
• 20:46
  to recognize basically them to overcome that, it's a bit more
• 20:52
  challenging and we need to focus on unusual kind of antigens.
• 20:59
  For instance, splice new epitopes that's in tumor, in
• 21:04
  solid tumors, for instance, Melanoma even shown that it's a
• 21:08
  group of new antigens that are less known.
• 21:11
  But the papers are published in Science by Michele Mishnos who
• 21:16
  they have shown that they can induce immune response and if
• 21:21
  you do vaccination they you get a good response, but because
• 21:25
  they are not very well known and they are not that frequent.
• 21:30
  They're not expressed by other cells also.
• 21:32
  That's very important, I guess, yeah.
• 21:34
  Yeah. So that's why I think there are
• 21:36
  we need to more a more precise approach on that.
• 21:40
  But I I believe vaccination has its own and also you know that
• 21:46
  for instance in Amsterdam or your.
• 21:50
  On. The roster is doing a
• 21:53
  vaccination with dendritic cells, which is also very
• 21:58
  encouraging results. So yes, I think the vaccination
• 22:03
  is also on a specific patients has a role.
• 22:07
  Yeah. OK, good.
• 22:10
  So I think we came very far around this very, very
• 22:14
  interesting subject. And I think we could talk about
• 22:16
  this for two more hours without maybe finding the right
• 22:20
  treatment still. But I think this is really worth
• 22:22
  working on. So I would like to thank you
• 22:25
  very much for getting this opportunity to hear your
• 22:29
  thoughts. Thank you very much for inviting
• 22:32
  me, and I hope it's useful for the members of the heart that
• 22:38
  they want to know more and hopefully we will hear more and
• 22:41
  more about these subjects in years to come.